Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Clinically used combination of radiation therapy and chemotherapy is the most common curative treatments for HNSCC, but causes many undesirable side effects and will incur resistance. Photodynamic therapy (PDT) is an effective anticancer procedure but its clinical application is limited due to the extreme light sensitivity o patients before and after treatment, the suboptimal reactive oxygen species generation efficiency, and the shallow tissue penetration of light (< 1 cm). Nanoparticle photosensitizers (PSs) can selectively accumulate in tumors and thus alleviate the light sensitivity issue. NIR triggered PDT and X-ray induced PDT (X-PDT) have the ability to combine the strengths of the improved tissue penetration depth of NIR and X-ray and the advantages of PDT for deep tumor treatment. We herein propose to develop an entirely new class of nanoparticle PSs based on nanoscale metal-organic frameworks (NMOFs) that have the ideal characteristics of tunable chemical compositions, crystalline structures, extremely high porosity, short-term stability, and long-term bio- degradability to enable NIR triggered PDT for superficial tumors and X-PDT for deep tumors. This project addresses the unmet needs in developing highly efficient and safe nanoparticle PSs that can have much broader clinical applications for cancer by NIR-triggered PDT or X-PDT. We propose the following aims: AIM 1: Synthesis and characterization of NMOFs for NIR triggered and X-PDT. We will optimize NMOF structures, particle sizes, and surface characteristics to achieve NIR-triggered PDT and X-PDT with improved efficiency. Efforts will also be made for scaled-up NMOF synthesis and surface functionalization to achieve long blood circulation times. AIM 2: Evaluation of NIR triggered PDT efficacy for HNSCC. The NIR-PDT efficacy of NMOFs will be evaluated against multiple HNSCC cell lines in vitro. We will investigate the in vivo toxicity and efficacy of one most potent NMOF identified at cellular level against HNSCC subcutaneous xenograft and orthotopic mouse models. AIM 3: Evaluation of X-ray induced PDT efficacy for HNSCC. The X-PDT efficacy of NMOFs will be investigated against HNSCC cells in vitro. For the in vivo studies, we will first evaluate the toxicity of the NMOFs and the X-PDT treatment alone. The in vivo anticancer efficacy will be carried out on both subcutaneous and orthotopic HNSCC mouse models with the two most potent NMOFs identified at cellular level. We will also apply state-of-the-art small-animal image-guided X-Ray delivery technology to enable image-guided X-PDT, toward translation to clinical radiotherapy